The long-term objective of the proposed project is to conduct a thorough examination of the evidence for susceptibility gene(s) for affective disorder in the Old Order Amish (OOA) using state-of-the-art analytic methods as yet unemployed in data generated from this population. The definitive localization of a vulnerability locus for affective disorder has not yet occurred in any population despite clear evidence of a genetic susceptibility to affective disorders provided by data from family, twin, and adoption studies. linkage analyses of affective disorder have been more challenging than originally anticipated due to the complicated relationship between phenotype and genotype. Nevertheless, attempts to identify vulnerability genes for other disorders with complex inheritance have met with success and have shown that a variety of techniques used in concert may be the most reasonable approach for these traits. Therefore, the specific aims of the current proposal are: (l) to search for extended haplotype sharing in distantly related individuals using a method developed for use in genetically isolated populations such as the OOA; (2) to conduct a genome-wide screen for susceptibility loci for affective disorder using non-parametric affected-pedigree-member or allele-sharing methods; and (3) to expand the traditional parametric linkage approaches used within the OOA to include low penetrance models, or the analysis of affected individuals only, and the generation of lod scores maximized over genetic parameters. Complete diagnostic data from the OOA will be provided by Janice A. Egeland, Ph.D. including annual updates. A full genome screen has been undertaken in the molecular genetic laboratory of Daniela S. Gerhard, Ph.D. at the Washington University School of Medicine and marker data spaced at 10cM intervals will be available to this project. The pedigree to be analyzed is comprised of 165 members, 125 of whom are genotyped and 41 of whom meet Research Diagnostic Criteria for major affective disorder. Another pedigree with sufficient power to replicate any potential linkages found in the first waves of analysis has been held in reserve and will be available for genotyping in the future. The ultimate goal of this research would be to provide information which could improve diagnosis, aid in the identification of additional genetic as well as environmental etiological factors, and facilitate treatment and prevention interventions.